According to the American Cancer Society, prostate cancer is the most commonly diagnosed cancer among men in the United States, other than skin cancer. The American Cancer Society estimates that approximately 186,000 new cases of prostate cancer were diagnosed, and approximately 29,000 men died of prostate cancer in the United States alone during 2008. Prostate cancer is thus the second-leading cause of cancer death in men in the United States, after lung cancer.
Metastatic prostate cancer is cancer that has spread beyond the prostate and surrounding tissues into distant organs and tissues. The majority of men who die from prostate cancer die from the consequences of metastatic disease. According to the National Cancer Institute, the median survival of patients with prostate cancer that has metastasized to distant organs is usually one to three years, and most such patients will die of prostate cancer. Metastatic prostate cancer is generally divided into two states: the hormone-sensitive state and the castration-resistant state (also referred to as the hormone-refractory state).
Testosterone and other male sex hormones, known collectively as androgens, can fuel the growth of prostate cancer cells. Androgens exert their effects on prostate cancer cells by binding to and activating the androgen receptor, which is expressed in prostate cancer cells. When they first metastasize to distant sites, most prostate cancers depend on androgens for growth. These prostate cancers are known as “hormone-sensitive” cancers. Accordingly, the leading therapies currently used for the treatment of metastatic prostate cancer are focused on diminishing, or antagonizing, the effects of androgens on prostate cancer cells. One approach utilizes so-called “anti-androgens,” which are molecules that block the interaction of androgens with the androgen receptor. Another approach is to reduce the amount of androgens produced in the body, primarily in the testes. This can be achieved surgically by removal of both testicles (orchiectomy) or through use of drugs known as luteinizing hormone-releasing hormone, or LHRH, agonist drugs, which lower the native production of testosterone in the testicles (sometimes called “chemical castration”).
Most metastatic prostate cancer initially is hormone-sensitive and thus responds to hormonal therapies. However, according to a study published in the Oct. 7, 2004 issue of The New England Journal of Medicine, virtually all hormone-sensitive metastatic prostate cancer undergoes changes that convert it to the castration-resistant state in a median of 18-24 months after initiation of hormonal therapy [Debes, J. et al. “Mechanisms of Androgen-Refractory Prostate Cancer.” New. England. J. Med. (2004), 351:1488-1490]. One of the important mechanisms by which prostate cancer cells switch from the hormone-sensitive to the castration-resistant state appears to be through overexpression of the androgen receptor. In experiments comparing gene expression in hormone sensitive and castration-resistant prostate cancer cells, an increase in androgen receptor expression was the only gene change consistently associated with castration-resistant disease [Chen, C. et al. “Molecular determinants of resistance to antiandrogen therapy.” Nat. Med. (2004), 10(1):33-39]. Once in this state, prostate cancers generally continue to grow in an androgen-dependent manner despite the reduction of testosterone production to very low (i.e., post-castration) levels. Prostate cancer in this state is known as “castration-resistant” prostate cancer, or CRPC. The switch from the hormone-sensitive to the castration-resistant state following initiation of hormonal therapy is generally determined based on either rising levels of prostate-specific antigen, or PSA, or documented disease progression as evidenced by imaging tests or clinical symptoms. Metastatic prostate cancer that has become castration-resistant is extremely aggressive; these patients have a median survival of only 10 to 16 months.
A primary reason that CRPC is so deadly is that it is difficult to treat. Because therapies currently used for the treatment of metastatic prostate cancer operate by reducing the ability of androgens to fuel the growth of prostate cancer cells, they generally are effective only on prostate cancers that remain hormone-sensitive by depending on androgens for growth. CRPC no longer responds to hormonal therapies that are effective in the hormone-sensitive state. To further complicate the situation, due to biological changes in prostate cancer that has entered the castration resistant state, drugs that initially block the androgen receptor and inhibit growth of hormone sensitive prostate cancer may have precisely the opposite effect and start to fuel the growth of CRPC. For example, Casodex® (bicalutamide), sold by AstraZeneca PLC, directly blocks the interaction of androgens with the androgen receptor and is the largest selling of the anti-androgen therapies. However, in an in vitro model of castration-resistant prostate cancer in which prostate cancer cell lines were genetically engineered to overexpress the androgen receptor (thus converting them from the hormone-sensitive to the castration-resistant state), Casodex® failed effectively to inhibit the androgen receptor in these cells, and in some cases it became a stimulant of the androgen receptor. These findings, which are consistent with the published human clinical experience with Casodex in CRPC, render Casodex® an ineffective therapy for the castration-resistant state of metastatic prostate cancer.
Compounds that bind the androgen receptor, the same target bound by Casodex® and other marketed drugs for metastatic prostate cancer, have been developed for use in the castration-resistant state of metastatic prostate cancer. These compounds bind the androgen receptor in a manner that renders them effective in treating cancers that have become refractory to currently used drugs. For example, certain compounds disclosed in U.S. Patent Application Publication Nos. 2007/0004753, 2007/0254933 (republished as 2008/0139634), and 2009/0111864 are novel small-molecule androgen receptor antagonists that inhibit androgen receptor function by blocking nuclear translocation of the androgen receptor and DNA binding.
The synthetic route to compounds of the invention, as described in the aforementioned U.S. patent application Publications, comprises the coupling of an isothiocyanate with an isobutyronitrile. The main drawbacks of the process as previously described include only a 25% yield of desired product being achieved in the final step, resulting in a 15% overall yield from commercially available starting materials. Moreover, each intermediate compound requires laborious column chromatography for purification, resulting in extended overall production time which is industrially disadvantageous. In comparison, the present invention described herein comprises a 50% overall yield, and any required purification is achieved by simple precipitation or crystallization means. Further, the present invention avoids the use of the extremely toxic reagent acetone cyanohydrin. As a result, the process according to the present invention is a safer process in which the amount of solvent is lowered, minimizing waste and environmental impact, the cycle time is reduced, and the throughput and overall yield of the process is increased.